5nky

From Proteopedia

Structure-activity relationship study of vitamin D analogs with oxolane group in their side chain

PDB ID 5nky

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Structural highlights

5nky is a 2 chain structure with sequence from Danio rerio and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.096Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

VDRA_DANRE Nuclear hormone receptor. Transcription factor that mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes. Regulates transcription of hormone sensitive genes via its association with the WINAC complex, a chromatin-remodeling complex. Plays a central role in calcium homeostasis.^[1]

Publication Abstract from PubMed

Synthetic analogs of 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) have been developed with the goal of improving the biological profile of the natural hormone for therapeutic applications. Derivatives of 1,25(OH)2D3 with the oxolane moiety branched in the side chain at carbon C20, act as Vitamin D nuclear Receptor (VDR) superagonists being several orders of magnitude more active than the natural ligand. Here, we describe the synthesis and biological evaluation of three diastereoisomers of (1S, 3R)-Dihydroxy-(20S)-[(2-hydroxy-2-propyl)-tetrahydrofuryl]-22,23,24,25,26,27- hexanor-1alpha-hydroxyvitamin D3, with different stereochemistry at positions C2 and C5 of the oxolane ring branched at carbon C22 (1, C2RC5S; 2, C2SC5R; 3, C2SC5S). These compounds act as weak VDR agonist in transcriptional assays with compound 3 being the most active. X-ray crystallographic analysis of the VDR ligand-binding domain accommodating the three compounds indicates that the oxolane group branched at carbon C22 is not constrained as in case of compound with oxolane group branched at C20 leading to the loss of interactions of the triene group and increased flexibility of the C/D-rings and of the side chain.

Structure-activity relationship study of vitamin D analogs with oxolane group in their side chain.,Belorusova AY, Martinez A, Gandara Z, Gomez G, Fall Y, Rochel N Eur J Med Chem. 2017 Jul 7;134:86-96. doi: 10.1016/j.ejmech.2017.03.081. Epub, 2017 Apr 2. PMID:28399453^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ciesielski F, Rochel N, Moras D. Adaptability of the Vitamin D nuclear receptor to the synthetic ligand Gemini: remodelling the LBP with one side chain rotation. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):235-42. Epub 2007 Jan 10. PMID:17218092 doi:http://dx.doi.org/10.1016/j.jsbmb.2006.12.003
↑ Belorusova AY, Martinez A, Gandara Z, Gomez G, Fall Y, Rochel N. Structure-activity relationship study of vitamin D analogs with oxolane group in their side chain. Eur J Med Chem. 2017 Jul 7;134:86-96. doi: 10.1016/j.ejmech.2017.03.081. Epub, 2017 Apr 2. PMID:28399453 doi:http://dx.doi.org/10.1016/j.ejmech.2017.03.081